Population pharmacokinetic-pharmacodynamic analysis of fluindione in patients.
OBJECTIVE
Fluindione is a vitamin K antagonist with a long half-life. This study was designed to investigate the pharmacokinetics and pharmacodynamics of multiple doses of fluindione in patients.


METHODS
In a learning group of 49 patients who began fluindione treatment, blood samples were taken 12, 18, or 24 hours after one, three, and five doses. Concentration of fluindione, activity of clotting factors II, VII, IX and X, prothrombin complex activity (PCA), and international normalized ratio (INR) were measured. An indirect-response pharmacodynamic model was used for each effect. A comprehensive analysis was performed with a nonparametric population approach. The model was evaluated in 24 other patients: blood samples were taken 24 hours after two, three, four, and six doses; and PCA and INR were observed.


RESULTS
Analysis of concentrations and clotting factor activities showed notably that (1) fluindione has a long half-life (median, 69 hours), and (2) concentration that inhibits the synthesis of the clotting factors by 50% varied for each factor, with a median ranging from 0.25 to 2.05 mg.L-1 for factors VII and II, respectively. The results obtained for INR and PCA were validated in the 24 subsequent patients.


CONCLUSIONS
The population approach allowed the comparison of several pharmacodynamic submodels. This first application of the indirect-response model to multiple oral anticoagulant doses in patients confirmed that both the pharmacokinetics and the pharmacodynamics of fluindione show substantial interindividual variability.
Mentré
F
F
INSERM U436, Génétique Cardiovasculaire Centre Hospitalo-Universitaire Pitié-Salpêtrière, Paris, France. mentre@biomath.jussieu.fr
Pousset
F
F
Comets
E
E
Plaud
B
B
Diquet
B
B
Montalescot
G
G
Ankri
A
A
Mallet
A
A
Lechat
P
P
D000925:Anticoagulants / Q000493:pharmacokinetics / Q000494:pharmacology*; D001779:Blood Coagulation Factors / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D006801:Humans; D008875:Middle Aged; D010630:Phenindione / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology
D000925:Anticoagulants; D001779:Blood Coagulation Factors; D010630:Phenindione; C017673:fluindione